Title

Author

Defense Date

2015

Document Type

Dissertation

Degree Name

Doctor of Philosophy

Department

Neuroscience

First Advisor

Raymond Colello

Abstract

Endogenous bioelectric fields guide morphogenesis during embryonic development and regeneration by directly regulating the cellular functions responsible for these phenomena. Although this role has been extensively explored in many peripheral tissues, the ability of electric fields to regulate wound repair and stimulate regeneration in the mammalian central nervous system (CNS) has not been convincingly established. This dissertation explores the role of electric fields in regulating the injury response and controlling the regenerative potential of the mammalian CNS. We place particular emphasis on their influence on astrocytes, as specific differences in their injury-induced behaviors have been associated with differences in the regenerative potential demonstrated between mammalian and non-mammalian vertebrates. For example, astrocytes in both mammalian and non- mammalian vertebrates begin migrating towards the lesion within hours and begin to proliferate after an initial delay of two days; subsequently, astrocytes in non-mammalian vertebrates support neurogenesis and assume a bipolar radial glia-like morphology that guides regenerating axons, whereas astrocytes in mammals do not demonstrate robust neurogenesis and undergo a hypertrophic response that inhibits axon sprouting. To test whether injury-induced electric fields drive the astrocytic response to injury, we exposed separate populations of purified astrocytes from the rat cortex and cerebellum to electric field intensities associated with intact and injured mammalian tissues, as well as to those electric field intensities measured in regenerating non-mammalian vertebrate tissues. Upon exposure to electric field intensities associated with uninjured tissue, astrocytes showed little change in their cellular behavior. However, cortical astrocytes responded to electric field intensities associated with injured mammalian tissues by demonstrating dramatic increases in migration and proliferation, behaviors that are associated with their formation of a glial scar in vivo; in contrast, cerebellar astrocytes, which do not organize into a demarcated glial scar, did not respond to these electric fields. At electric field intensities associated with regenerating tissues, both cerebellar and cortical astrocytes demonstrated robust and sustained responses that included morphological changes consistent with a regenerative phenotype. These results support the hypothesis that physiologic electric fields drive the astrocytic response to injury, and that elevated electric fields may induce a more regenerative response among mammalian astrocytes.